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Ultrasonic microelectromechanical system for microfluidics, cancer therapeutics and sensing applications

ULTRASONIC MICROELECTROMECHANICAL SYSTEM FOR
MICROFLUIDICS, CANCER THERAPEUTICS AND SENSING
APPLICATIONS
by
Lingtao Wang
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
􀀁􀄀 􀀁􀄀 􀀁􀄀 􀀁􀄀 􀀁􀄀􀀁􀄀􀀁􀄨(ENGINEERING)
December 2013
Copyright 2013 Lingtao Wang

This thesis presents ultrasonic Micro-Electro-Mechanical Systems (MEMS) designed for microfluidic, biomedical and physical sensing applications, including a nozzleless micro-ejector with “phase-varied” and “dual-frequency” acoustic lens for the electrical control of droplet direction; high-frequency Self-Focusing Acoustic Transducers (SFAT) for three-dimensional localized cell lysis for cancer therapeutics; and the design of sensing system with a phase-locked loop frequency shift detection for a Doppler velocity sensing system and for FBAR-based oscillator sensors. ❧ For a multi-directional acoustic ejector with capability of electrical control on the droplet ejection angle, a novel design of the acoustic lens with “phase-varied” and “dual-frequency” patterns are developed and tested. With the novel lens, the direction of the droplet ejection depends monotonically on the operating frequency of the driving signal. The newly developed ejector consistently ejects uniform droplets in diameter of 70 µm, with electrical control of the directional angle from -30° to 35° (with respect to normal direction of liquid surface plane) as the operating frequency is varied from 16.78 MHz to 19.08 MHz. ❧ For three-dimensional localized cell lysis for cancer therapeutics, Self Focusing Acoustic Transducers (SFAT) are designed and fabricated for focusing acoustic energy within an area of 100 μm in diameter at 800 μm focal length for applications requiring high spatial resolutions. Then, the SFAT with large focal area of 1 mm and long focal length of 10 mm are demonstrated for fast ultrasound treatments with large area coverage in a three-dimensional environment. In order to minimize potentially non-specific heat or cavitation effects by acoustic irradiations, operational parameters are optimized to study bio-effects of the device in the absence of tissue heating or biological effects due to cavitations. In the case of 2D monolayer cells, the Acoustic Intensity Thresholds (AIT) for cell lysis in various cell lines representative of benign and malignant prostate, breast and skin cells are investigated. And it is observed that lower AIT’s in cancer cells over non-malignant variants. Actin staining of cytoskeletal structures indicates an association between a pattern of diffuse and less organized actin filaments with decreased AIT. Moreover, the same trend of decreased actin organization and decreased AIT is observed following treatments of changing actin patterns in the MCF-10A breast epithelial cell line. These results suggest that biomechanical properties make malignant cells specifically sensitive to cytolysis caused by this form of acoustic energy. In the case of 3D cell spheroids, the acoustic intensity thresholds (AITs) of spheroids for cancer-specific cytolysis of malignant cells (breast cancer MCF-7 and prostate cancer 22RV1) are investigated. According to experiments with the spheroids in the 3D Matrigel environment, the crosslinks between Matrigel and spheroids greatly increase AITs of 22RV1 and MCF-7 cell spheroids from 0.11 W/cm² to 11.10 ~ 15.14 W/cm². In addition, in both “unsolidified” (without crosslink) and solidified (with crosslink) Matrigel environments, spheroids of non-malignant cell line MCF-10A are not lysed even with two to three times higher acoustic intensities than the AITs of MCF-7. Therefore, the general trend associating a lower AIT with a more malignant still stands for MCF-7 and MCF-10A 3D cell spheroids in the 3D Matrigel environment. ❧ For the design of ultrasonic sensing systems, a novel, highly-sensitive ultrasonic Doppler velocity sensing system, and a hand-held, low-cost but highly sensitive sensing system built with an FBAR-based oscillator are designed, fabricated and tested. The ultrasonic velocity sensing system is a compact velocity sensing system, in which MEMS ultrasonic transducers are incorporated with phase-locked-loop (PLL) circuitry for frequency detection and signal processing. The achieved voltage-velocity sensitivity is 0.22 V/(mm/s) and the minimum detectable velocity is 0.67 mm/s, corresponding to 0.11 Hz in Doppler frequency. Also, the output of the PLL is a DC voltage linearly related to the velocity, and there is no need to convert the frequency shift to analog voltage. The FBAR-based sensor with a phase-locked-loop (PLL) for ppm-level detections and signal processing is a novel potable sensing system for remote sensing applications. The achieved voltage-frequency sensitivity is 1.035 V/kHz with the minimum detectable frequency shift of 4.81ppm (5.21kHz), and the dynamic range is 134 ppm (145kHz). Also, the output of the sensing system is purposely designed to be a DC voltage that is linearly related to the frequency shift. To our knowledge, it is the first FBAR-based sensing system that converts frequency shift to DC voltage.

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ULTRASONIC MICROELECTROMECHANICAL SYSTEM FOR
MICROFLUIDICS, CANCER THERAPEUTICS AND SENSING
APPLICATIONS
by
Lingtao Wang
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
􀀁􀄀 􀀁􀄀 􀀁􀄀 􀀁􀄀 􀀁􀄀􀀁􀄀􀀁􀄨(ENGINEERING)
December 2013
Copyright 2013 Lingtao Wang